文章：

FLT3在造血恶性肿瘤中的作用

The role of FLT3 in haematopoietic malignancies

原文发布日期：2003-09-01

DOI: 10.1038/nrc1169

类型: Review Article

开放获取: 否

要点：

1. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) involved in the proliferation, differentiation and apoptosis of haematopoietic cells. It is mainly expressed by early myeloid and lymphoid progenitor cells.
2. Many cells of the haematopoietic system produce FLT3 ligand (FLT3L), which promotes dimerization and activation of FLT3. The activated receptor then activates the phosphatidylinositol 3-kinase (PI3K) and RAS signal-transduction cascades.
3. The FLT3 internal tandem duplication (ITD) results from a head-to-tail duplication of 3–400 base pairs in exons 14 or 15, which encode the juxtamembrane domain of FLT3.
4. Point mutations in FLT3 occur in heavily conserved areas of the intracellular tyrosine-kinase domain (TKD), homologous to point mutations that are seen in other RTKs such as KIT and FMS.
5. FLT3 mutations are the most frequent genetic lesion seen in acute myeloid leukaemia (AML). The prevalence of FLT3 ITDs is 15–35%, with an additional 5–10% of patients having FLT3 TKD mutations.
6. Both types of FLT3 mutation cause ligand-independent activation of the receptor and activation of downstream signalling pathways.
7. The presence of a FLT3 ITD is associated with poor clinical outcome in both paediatric and adult patients with AML.
8. Several drugs that target FLT3 are in early clinical trials.

要点翻译：

1. FMS样酪氨酸激酶3（FLT3）是一种受体酪氨酸激酶（RTK），参与造血细胞的增殖、分化和凋亡。它主要由早期髓系和淋巴祖细胞表达。
2. 造血系统中的许多细胞会产生FLT3配体（FLT3L），该配体可促进FLT3的二聚化和激活。激活后的受体进而启动磷脂酰肌醇3-激酶（PI3K）和RAS信号转导级联反应。
3. FLT3内部串联重复（ITD）源于第14或15外显子（编码FLT3的近膜结构域）出现3-400个碱基对的头尾重复。
4. FLT3的点突变发生在细胞内酪氨酸激酶结构域（TKD）的高度保守区域，与KIT、FMS等其他RTK中观察到的点突变具有同源性。
5. FLT3突变是急性髓系白血病（AML）中最常见的遗传学异常。FLT3 ITD的发生率为15%-35%，另有5%-10%的患者存在FLT3 TKD突变。
6. 两类FLT3突变均可引起受体不依赖配体的自主激活，并启动下游信号通路传导。
7. FLT3 ITD的存在与儿童及成人AML患者的不良临床预后相关。
8. 目前已有多种靶向FLT3的药物进入早期临床试验阶段。

英文摘要：

Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in ∼25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.

摘要翻译： 

正常造血细胞通过复杂的系统调控增殖、分化与死亡。其中，增殖的调控部分依赖于配体诱导的受体酪氨酸激酶激活，后者再通过RAS通路向下游效应器传递信号。近期研究发现，编码受体酪氨酸激酶的FMS样酪氨酸激酶3（FLT3）基因突变是急性髓系白血病（AML）中最常见的遗传异常，约见于25%的病例。探究这些FLT3突变导致细胞失控增殖的机制，有助于深入理解细胞癌变过程，并为新药研发提供思路。

原文链接：

The role of FLT3 in haematopoietic malignancies